Furthermore, a Cochrane Review comparing clozapine to second generation antipsychotics found them to be of similar efficacy and newer second generation antipsychotics could be more effective than clozapine if non-refractory patients are considered (Leucht et al 2013, Asenjo Lobos et al 2010, Leucht et al 2009, Davis et al 2003).

This new network meta-analysis looks at the efficacy, acceptability, and tolerability of antipsychotics for treatment-resistant schizophrenia.

Methods and participants

The analysis considered:

All published and unpublished single-blind and double-blind randomised controlled trials (RCTs, >3 weeks)

Of adult patients with a treatment-resistant form of schizophrenia, schizophreniform disorder, or schizoaffective disorder

With any antipsychotic monotherapy, in any dose or formulation, in any country, that was compared to any other antipsychotic or placebo.

Results

Forty unique blinded RCTs with 5,172 unique participants with an average duration of illness of 16.2 years, were published between 1968 and 2012.

The mean dose of the 12 antipsychotics included in the analysis was 794 mg/d in chlorpromazine equivalents, mostly involving clozapine, haloperidol, olanzapine and risperidone.

Severe inconsistency was identified between direct and indirect evidence because of pre-1990 papers and big changes in antipsychotic trials. Consistency is essential for network meta-analyses, so 5 papers published before 1990 were removed.

Here are the main findings as summarised by the authors:

A certain pattern of superiority was found for olanzapine, clozapine, and risperidone in various efficacy outcomes, such as mean change in overall and positive symptoms, response rates, and dropouts owing to inefficacy, but treatment efficacy differences were not definitive and clozapine was no more efficacious than most other second-generation antipsychotics, and this was not an artefact of using the NMA [network meta-analysis]. Although substantial evidence was available for clozapine, haloperidol, olanzapine, and risperidone, data on the other included antipsychotics were limited.

Meaning: Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia.

Rankings based on primary outcomes:

Olanzapine

Ziprasidone 2 studies (n = 453)

Clozapine

This well conducted study shows that we still don’t really know which antipsychotics work best for treatment-resistant schizophrenia.

Critique

The main criticism of this paper is that it gives no firm findings that can be applied in practice. Before reading this paper, a clinician would go through medicines by trial and error before a patient settles on the right one. After reading this paper the process is the same. Do the results mean clozapine should no longer be used for its “apparently” poor risk to benefit ratio? Or should it be used earlier, i.e. not a last resort?

It feels as though the authors were aiming to (dis)prove clozapine’s superiority to other antipsychotics, however, they established an analysis where major clozapine studies would not be included. Clozapine was generally superior in several unblinded clinical and cost-effectiveness studies (McEvoy et 2006, Essock et al 2000, Lewis et al 2006), whose results have been confirmed in real-world observational studies (Nyakyoma et al 2010, Ciudad et al 2008) with hard endpoints such as hospitalisation and number of inpatient days (Ringbäck et al 2014), none of which were included here.

Even if you could say which drug is best, what would it be best for? Schizophrenia presents on a spectrum. It is unclear which part of the spectrum we would be treating. How we classify/diagnose patients needs to change before we say which drug is best. This may have played a role by averaging out the results of the study.

The criteria of treatment resistance in this analysis varied from partial nonresponse to high levels of treatment resistance, differences the analysis was not sensitive to. Consequently, it is possible that clozapine’s lack of consistent superiority was due to the rare inclusion of patients with the most treatment-resistant disease in blinded RCTs. The same explanation could apply to clozapine’s dramatic superiority found in the study by Kane et al (Kane et al 1988a, Kane et al 1988b), which only included patients who were considered “beyond the reach of conventional therapy” (Kane et al 1988b). In the analysis, most included studies were conducted on less severely ill patients with more onerous consenting procedures and commercialisation of the research conduct.

Network meta-analysis has been criticised because it includes indirect evidence, which adds another level of complexity and assumptions.

Enough studies examined clozapine, olanzapine, risperidone, and haloperidol, but, for others the body of evidence was small and conclusions on them are not robust.

Where does this new evidence leave people living with treatment-resistant schizophrenia?

Murtada is a practicing pharmacist with over 10 years experience in the industry and is currently working for a pharmaceutical consultancy. He gained his MPharm at the School of Pharmacy, UCL, and has recently completed a PhD in Biotechnology at the University of Cambridge. His PhD project attempted to proteomically characterise bipolar disorder and cross-compare the protein signature in the brain and the periphery. He has contributed to several published research articles in peer-reviewed journals.